Stopping the Brain From Hurting Itself

One-third of stroke survivors never recover enough brain function to live on their own. Now scientists think they know why. Once a stroke kills a swath of brain cells, a neurotransmitter known as GABA impairs the surviving, apparently healthy, brain tissue. Targeting GABA could help a stroke-afflicted brain better overcome its damage, the researchers suggest.

When a stroke hits, physicians have few options. If they catch it early enough, they can administer the clot-busting drug tPA to keep even more brain cells from dying—but tPA is not appropriate for all types of stroke. Physicians can also prescribe physical therapy, which can occasionally help recover impaired motor function. Yet there are no approved drugs that help the brain heal.

For its part, the brain appears to try a sort of natural drug therapy to limit the spread of damage. It releases extra amounts of GABA, which reduces the firing of neurons. GABA initially prevents stroke-damaged brain tissue from becoming overexcited and dying. But University of California, Los Angeles (UCLA), investigators led by Thomas Carmichael, a specialist in stroke, and Istvan Mody, an expert in inhibition, wondered whether GABA might also interfere with the brain's plasticity, the ability of healthy regions to take over for injured ones.

Previous studies had tried to address this question, but they produced confusing results. The UCLA team hypothesized that others had failed to distinguish between two types of inhibition—phasic, in which GABA acts upon specific receptors at nerve cell sites called synapses, and tonic, in which the neurotransmitter acts on other receptors elsewhere on the nerve cell. "We looked at all the properties of neural transmission after stroke, and we found the most prominent change was an increase in the tonic form of inhibition in the cortical region next to the stroke damage," says graduate student and study co-author Ben Huang. So the group gave stroke-afflicted rodents a drug that could specifically block GABA-mediated tonic inhibition but left phasic inhibition intact. The mice had suffered damage in areas that control movement, yet they recovered about 50% more function in their limbs than similar rodents treated with a control therapy, the team reports online today in Nature.

The findings suggest a new, potentially therapeutic window for treating stroke, says Carmichael. Physicians might be able to give a GABA-blocking drug after stroke, for example. The key would be proper timing: after tonic inhibition had initially protected as many brain cells as possible but before it begins interfering with the brain's recovery attempts. The class of drugs used by the UCLA team to block GABA receptors is currently in clinical development for other conditions, such as memory loss, and has been well-tolerated in small studies. However, the drugs have not yet been tested on stroke patients. Clinical trials are a long way off, cautions Carmichael, because more animal studies by other labs must be performed first.

Nonetheless, other neuroscientists say the work offers a new direction for developing stroke drugs. "The result is very gratifying because for many, many years people have focused on excitatory synapses and excitatory connections in terms of brain plasticity," says Takao Hensch, a developmental plasticity researcher in the Molecular and Cellular Biology Department at Harvard University. "It's only in the recent past that we've started to appreciate that the balance of excitation to inhibition is what's important."